From bile acids to yes-associated protein: A bidirectional switch for cholangiocarcinoma therapy

Abstract

Cholangiocarcinoma (CCA) is characterized by high invasiveness, early metastasis, and chemotherapy resistance, with a 5-year survival rate persistently below 20%. Current therapies are limited to surgery and a few chemotherapeutic options, highlighting an urgent need for actionable molecular targets and personalized strategies. In the recent issue of World Journal of Gastrointestinal Oncology, Hu et al report that glycochenodeoxycholic acid activates yes-associated protein (YAP) by inhibiting mammalian Ste20-like kinases/large tumor suppressor kinases (MST/LATS) phosphorylation, thereby promoting proliferation, invasion, and suppressing apoptosis, whereas deoxycholic acid enhances MST/LATS phosphorylation to block YAP nuclear entry, inhibiting tumor growth and inducing apoptosis. Given that the conversion between conjugated and unconjugated bile acids is fundamentally governed by intestinal microbial metabolism, this finding underscores the critical regulatory role of the gut microbiota. YAP modulators can reverse these bile-acid effects in both directions, establishing the “bile acid-Hippo-YAP” axis as an actionable driver. This study is the first to demonstrate the opposing roles of these two bile acids within the same model system, providing a mechanistic basis for CCA heterogeneity and suggesting that identifying bile acid biomarkers, manipulating the gut microbiota-bile acid metabolism or combining YAP-targeted drugs could offer novel strategies to overcome the therapeutic bottleneck in CCA. However, the use of a single cell line, one animal model, and the lack of immune microenvironment data limit generalizability; other bile acid species and cross-talk pathways were not explored. The commentary concludes that future work should further validate these findings.

Keywords: Bile acids; Yes-associated protein; Cholangiocarcinoma; Gut microbiota; Therapeutic targets

Core Tip: Bile acids (BAs) exert complex, structure-dependent regulatory effects on the Hippo-yes-associated protein pathway in gastrointestinal malignancies. These editorial highlights a pivotal “bidirectional switch” mechanism where glycochenodeoxycholic acid and deoxycholic acid induce opposing outcomes in cholangiocarcinoma. By integrating the physicochemical distinctions between conjugated and unconjugated BAs with their dynamic interplay in gut microbiota dysbiosis, we propose a multidimensional “microbiota-BA-Hippo” regulatory network. Targeting this axis offers novel precision therapeutic strategies for managing cholangiocarcinoma and metabolic disorders.